The aim of this Program Project is to develop reliable, safe, and rational gene transfer procedures to repair or replace neurotransmitter function in relevant animal models of Alzheimer's Disease (AD). Project 1 focuses on the uses of lentivirus to replace age related decline of the cholinergic system in aged rats by over expression of the CHAT gene regionally; protecting against age related cholinergic cell loss; and testing the therapeutic effects of these genes in the mouse by over expressing a human mutated form of APP. Project 4 will use lentivirus to over express Cre recombinase in transgenic mice with the LOX sites surrounding the CHAT, NGF and P75 genes respectively, and will cross mice with homologous knockout of p75 and NGF gene, with mice over expressing a human mutation of the APP gene, to directly determine the interaction between these related genes. Project 5 will test the hypothesis that development of Alzheimer's disease is due to multiple deficits or "stresses" which lead to pathology. Project 3 will optimize in vivo vectors for gene therapy in primates by comparing AAV and lentivirus for amount, duration and safety of gene expression. In Project 6 recombinant lentiviral vectors expressing mutant PS1 or APP in developing transgenic models of amyloid deposition in the brain, will examine the interactions of these genes in vivo. The Vector Core, will support high recombinant vectors to all projects. The Projects/Cores in this PPG have been chosen for their relevance in addressing these problems and securing a rational approach to gene therapy in AD. The interdependency of resources and skills between Projects/Cores, as well as our past success with this PPG, support the argument that the Program Project is the most efficient and cost-effective way to address these issues.